This is a prospective cohort study where HIV-infected and uninfected children will be enrolled between 6 weeks and 9 months of age and followed to the age of 21 months. All HIV-infected children will be given trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis as of 6 weeks of age. HIV-uninfected children born to HIV-infected mothers will be given TMP/SMX prophylaxis for the duration of breastfeeding and then randomized to the continuation of TMP/SMX or discontinuation of TMP/SMX prophylaxis. HIV-uninfected children born to HIV-uninfected mothers will not be given TMP/SMX prophylaxis. Study participants will be followed for all of their health care needs in a designated study clinic. All mother-child pairs will receive a basic care package including insecticide-treated bednets (ITNs) at enrollment. All HIV-infected mothers and children will receive antiretroviral therapy if eligible according to standardized World Health Organization (WHO) criteria. Study participants 4 months of age or older and at least 5 kg will be randomized to treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) at the time of their first diagnosis of uncomplicated malaria. Study participants will receive the same antimalarial treatment regimen for all future episodes of uncomplicated malaria. Study participants less than 4 months of age or less than 5 kg diagnosed with malaria and all episodes of complicated malaria will be treated with quinine in accordance with local guidelines.

The investigators will test the hypotheses that:

1. TMP/SMX prophylaxis is highly effective in preventing malaria in both HIV-infected and HIV-uninfected children

2. The use of TMP/SMX prophylaxis is associated with an increased risk of infection with malaria parasites containing antifolate resistance-conferring mutations.

3. The use of antiretroviral (ARV) drugs is associated with a decreased incidence of malaria.

4. The efficacy, safety, and tolerability of AL and DP for the treatment of uncomplicated malaria differ.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Factorial Assignment, Safety/Efficacy Study

Intervention(s) in this Clinical Trial

• Drug: Dihydroartemisinin-piperaquine
  • Once daily for 3 days, given in fixed dose tablets (40 mg dihydroartemisinin + 320 mg piperaquine) according to weight-based guidelines
• Drug: Artemether-lumefantrine
  • Dosed twice daily for 3 days, given in fixed dose tablets (20 mg artemether + 120 mg lumefantrine) according to weight-based guidelines
• Drug: Trimethoprim-sulfamethoxazole
  • Once daily dosing according to weight based guidelines

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Treatment for episodes of uncomplicated malaria
• Active Comparator: 2
  • Treatment for uncomplicated malaria
• Experimental: A
  • Prevention of malaria in HIV uninfected, exposed children
• No Intervention: B
  • Prevention of malaria in HIV uninfected, exposed children

Primary Measures

• Incidence of clinical episodes of malaria
• Risk of treatment failure at Day 28 defined as any early treatment failure or late clinical/parasitological failure adjusted and unadjusted by genotyping to distinguish recrudescence (treatment failure due to drug resistance) and new infections

Secondary Measures

• Prevalence of mutations known to confer resistance to antifolate drugs in pretreatment samples from patients diagnosed with malaria
• Risk of adverse events

Inclusion Criteria:

• 1. Age 6 weeks to 9 months
• 2. Documented HIV-1 status of mother and child
• 3. Agreement to come to the study clinic for any febrile episode or other illness
• 4. Agreement to avoid medications administered outside the study protocol
• 5. Guardian age 18 years or older (no age limit for parents)
• 6. Parent or guardian willing to provide informed consent
• 7. Residence within a 30 km radius of the study clinic

Exclusion Criteria:

• 1. HIV-exposed infants who have already stopped receiving TMP/SMX as a result of having stopped breastfeeding and having been tested HIV-negative before screening
• 2. Intention to move more than 30 km from the study clinic during the follow-up period
• 3. History of allergy or sensitivity to AL or DP or TMP/SMX
• 4. Active medical problem requiring in-patient evaluation at the time of screening

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 6 Weeks

Maximum Age for this Clinical Trial: 9 Months

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: University of California, San Francisco

Overall Clinical Trial Officials and Contacts

Grant Dorsey, MD, PhD Principal Investigator University of California, San Francisco  

Overall Contact: Emmanuel Arinaitwe, MBChB 256772989818 emmy3md@yahoo.com

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00527800

Study ID Number: DDCF 20060058

ClinicalTrials.gov Identifier: NCT00527800

Health Authority: Uganda: National Council for Science and Technology

MU-UCSF Research Collaboration website